Adenoside A2A receptors (also know as ADORA2A) are members of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices. The receptor is mediated by G proteins, which activate adenylyl cyclase and is abundant in basal ganglia, vasculature and platelets and it is a major target of caffeine. The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. The A2A receptor is also expressed in the brain, where it has important roles in the regulation of glutamate and dopamine release. The A2A receptor signals in both the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists as useful in neurodegenerative disorders, such as Parkinson's disease.
There has been progressive development of compounds that are more and more potent and/or selective as agonists of A2A adenosine receptors (AR) based on radioligand binding assays and physiological responses. For example, U.S. Pat. Nos. 6,232,297 and 7,214,665 and U.S. Patent Application Publication Nos. 2006/004088, 2006/0217343, 2006/0040889 and 2007/0270373 all describe compounds having the general formula:
wherein R contains a ring. These compounds are reported to be A2A agonists.
U.S. Pat. No. 6,914,053 describes compounds of the following formula:
wherein E can be a variety of linear and cyclic groups and R″ is an alkoxy or cycloalkoxy group. The compounds described therein are said to be A3 agonists.
In U.S. Application Patent Publication No. 2006-0100169, International Application Publication Nos. WO 2006/015357 and WO 2006/101920 and Neuroscience, 141, 2029-2039 (2006), the compound 4-{3-[6-amino-9-((2R,3R,4S,5S)-5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]-2-propynyl}-piperidine-1-carboxylic acid methyl ester, which is adenosine derivative, is disclosed and the compound is suggested to be useful as an anti-inflammatory agent, a coronary artery vasodilator, a neuroprotective agent or the like.
In International Application Publication No. WO 03/029264 and Neuroscience, 141, 2029-2039 (2006), the compounds 4-{3-[6-amino-9-((2R,3R,4S,5S)-5-ethylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]-2-propynyl}-piperidine-1-carboxylic acid methyl ester and 4-{3-[6-amino-9-((2R,3R,4S,5S)-5-ethylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]-2-propynyl}-piperidine-1-carboxylic acid isobutyl ester, both of which are adenosine derivatives, are disclosed, and in Japanese Patent Application Publication No. 2002-536300, the compound 4-{3-[6-amino-9-((2R,3R,4S,5S)-5-ethylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]-2-propynyl}-cyclohexane-1-carboxylic acid methyl ester, which is adenosine derivative, is disclosed. Further, in these documents, these compounds are suggested to be useful as anti-inflammatory agents.
Despite the increasing development of adenosine A2A receptor agonists, as described above, only one, regadenoson, has been approved for use in the United States as a coronary vasodilator. Typical issues involved with administration these compounds include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases possibly due to receptor desensitization or to low receptor density in the targeted tissue. Therefore, it is important to continue to synthesize and test additional A2A receptor agonists in order to develop new and improved therapeutic agents.